Our ten-year study of nondiabetic animals and humans shows that the glucagon response to insulin-induced hypoglycemia (IIH) is largely autonomically mediated. Since this specific glucagon response is lost early in type 1 diabetes, an early autonomic defect may be responsible. Indeed, we demonstrated an early sympathetic islet neuropathy (eSIN) in BB diabetic rats, diabetic NOD mice and now in human subjects with type 1 diabetes. Specific Aim #1: Determine if the loss of islet sympathetic nerves in human type 1 diabetes relates to their impaired glucagon responses. We will quantify the loss of islet nerves in autopsy samples from type 1 diabetic humans and determine if an impairment in this sympathetic A-cell pathway relates to the impairment of their glucagon response to IIH. Specific Aim #2: Determine if injury to the peri-islet Schwann cells (pSC), which protect and sustain islet sympathetic nerves, is the mechanism by which eSIN occurs. First, we will relate differing degrees of pSC injury to islet nerve loss in non-obese diabetic (NOD) mice. Second, we will administer glial toxins to determine if chemical injury to pSC causes nerve loss. Third, we will determine if this nerve loss is sufficient to impair the function of the sympathetic A-cell pathway. Finally, we will determine if this mechanism is islet- specific or autoimmune-specific by repeating these studies in the submandibular gland of the NOD mouse Specific Aim #3: Determine if restoring the islet nerves in BB diabetic rats corrects their impaired glucagon response to IIH. We will restore islet innervation by use of viral vectors encoding nerve growth factor while suppressing recurrent autoimmune attack on the islets and their ingrowing nerves. We will measure glucagon responses to IIH both before and after the reinnervation of the islets. Significance: Establishing that eSIN impairs the glucagon response to IIH and that reinnervation of the islet restores this response will provide new insight into the mechanism by which this response is lost in type 1 diabetes. Restoring the glucagon response to IIH will allow more intensive treatment of patients with type 1 diabetes which will in turn help prevent the long-term complications of this disease.